1. Field of the Invention
The present invention relates to stabilised compositions having antibacterial, anti-viral and/or antifungal activity, to a method of producing such compositions, medical devices having a coating comprising such compositions, and the use of the stabilised compositions for producing a wound dressing, an ostomy appliance, an incontinence device, other medical devices or hydrophilic coatings.
The antiseptic activity of silver compounds is a well known property which has been utilised for many years. The bacteriostatic and fungistatic effect is caused by the silver ion and a simple compound which has been used clinically is for instance silver nitrate. Silver nitrate in concentrations of 0.5-1% in water shows disinfectant properties and is used for preventing infections in burns or for prophylaxis of neonatal conjunctivitis. For another silver compound, silver sulfadiazine, the antibacterial effect of the sulfadiazine molecule is further enhanced by the complexing with the disinfecting silver ion. In contrast to the silver nitrate, the solubility of the silver sulfadiazine complex is low and hence, both of the two active parts are only present in solution in low concentrations but may be present over a longer period of time before being washed out at site to be treated. The silver sulfadiazine is intensively used in the treatment of wounds, in particular burns, under the trademarks Silvadene® and Flamazine®. Silver-protein-combinations are yet other antiseptic formulations which have been used in low concentrations as eye drops.
2. Description of the Related Art
Bacteriostatics based on the silver ion are further used in various medical devices. One example of such application is the use in the wound dressing sold by Johnson & Johnson under the trademark Actisorb® which is an activated charcoal cloth dressing. Another example is the wound dressing sold under the trademark EZ-Derm by Genetic Laboratories which dressing is a modified pigskin impregnated with a soluble silver compound intended for treatment of burns. A number of patents discloses compositions or devices showing antiseptic properties based on contents of silver compounds. EP 272 149 B1 discloses a medical dressing of the ‘hydrocolloid’ type containing and releasing active components. Silver chloride is a specific antiseptically acting compound mentioned in this patent.
A specific advantage in using the silver ion as bacteriostatic agent is the general lack of formation of bacterial tolerance to the compound. This is in contrast to many types of antibiotics. However a major drawback when using ionic silver for bacteriostatic purposes is the reduction of the ion to free silver which results in dark staining. Such staining has been reported to give potentially permanent pigmentation of the skin, the so-called argyria. It is commonly recognised that silver containing compounds will discolour by influence of light and or heat, and it will often be found that sterilisation by radiation may lead to a unsatisfactory change of the colour of a composition in which it is comprised, irrespective of the use in a solution, cream or gel or a medical device. Furthermore, such antibacterial compositions are often intended used in connection with medical or cosmetic products under circumstances where a discoloration is very unfortunate and potentially precluding for the use.
Recently, principles of antimicrobial metal-based compositions being photo stable, have been disclosed in U.S. Pat. No. 5,326,567 to Capelli and in U.S. Pat. No. 5,429,819 to Oka. In U.S. Pat. No. 5,326,567 a ‘host-guest’ relationship between silver ions and acyclic polyethers is accomplished through the use of excess of halide ions. In U.S. Pat. No. 5,429,819 is disclosed a photo-stable composition comprising a complex of the silver ion with a thiosulphate salt carried on a porous particulate carrier. In U.S. Pat. No. 3,911,115 (DE patent No. 22 60 536) a cycloheptaamylose (β-cyclodextrin) alkanol amine compound is claimed to posses stabilising effect on silver. However, in praxis the cycloheptaamylose alkanol amine complex is not effective in preventing discolouring. In U.S. Pat. No. 5,298,624 Lasker claims stable organometallic complexes of 5,5-diphenyl-2,4-imidazolidenedione (diphenylhydantoin) used as biocides. One such material is the silver-diphenyl hydantoin complex, which, however, it is poorly soluble in water. In U.S. Pat. No. 2,336,131 Schaffer disclose the formulation of silver allantoinate for antibacterial use. The compound is intended for medical use. However the compound does not show high stability against light. In U.S. Pat. No. 3,930,000 Margraf discloses silver-zinc allantoinate for topical use for control of bacteria and fungi. These compound, however, show a low solubility. In International Published Patent Application No. WO 00/09173 Pedersen et al teaches the stabilisation of silver by complexing with amines presenting a lone pair of electrons.
It is commonly recognised that compounds containing silver will discolourise in presence of light and/or heat, as well as it often will be found that radiation sterlisation process will lead to a dissatisfactory change of colour of the composition in which it is comprised whether it is in a cream or a gel or a medical device. Moreover, such antibacterial compositions are often intended for use for medical or cosmetic purposes under which circumstances a discoloration is very unfortunate and potentially prevents the use of silver ions for said use.
It is an object of the present invention to provide complex structure rendering silver ions stable against loss of the antiseptic activity and against darkening due to reduction of the silver ions or the formation of darkly stained sparingly or insoluble silver compounds. Furthermore, it is an object to provide a complex structure rendering silver ions available sufficiently quickly and in a sufficiently high and lasting concentration to ensure that an effective antiseptic activity is obtained. Still further it is an object to provide a method for preparing such complexes without losing the antiseptic activity of the silver ions. Further it is the objective to incorporate such into entities in combination with hydrophilic polymers, e.g. in hydrocolloid particles or coatings enabling a sufficient release of silver for the establishment of a bactericidal burst.
Such entities may be medical devices or instruments like catheters, guide-wires, wound dressings or similar.
The use of the silver complex of diphenyl hydantoin as taught by Lasker has the advantage of easy processing and for certain applications slow release. However, it is a major drawback that the compound has low solubility and lacks sufficient stability against irradiation and light. The silver allantionate likewise show low stability against light and has limited solubility. Especially when the compound is used in combination with hydrophilic polymers often used in the context of medical devices it may be impossible to obtain a high release of silver due to low solubility of the compound in biological environments and similarly impossible to incorporate such in the device.
It has surprisingly be found that certain silver complexes comprising silver and a ligand selected from the group consisting of 5,5-disubstituted hydantoins in which the substituents do not comprise conjugated unsaturated bonds and barbituric acid and derivatives thereof possess very good stability.